Germinal center (GC) B-cell lymphomas are clinically and genetically heterogeneous disorders. The incidence of the most common GC B-cell lymphomas has increased dramatically in recent years, with a 50% rise in the last generation. The participants of this PO1 believe that additional major breakthroughs in these increasingly common diseases will require a more complete understanding of critical underlying pathogenetic events. For this reason, we propose to address the following hypotheses in this competitive renewal application: 1) defects in DMA damage repair and deregulated immunoglobulin gene rearrangement predispose to oncogenic translocations and the development of lymphomas (F. Alt, Project 1);2) tonic signaling via the B-cell receptor (BCR) pathway and constitutive activation of the canonical and alternative NFicB pathways increases the survival of GC B-cell lymphomas (K. Rajewsky, Project 2);3) deregulated expression of the essential GC transcription factor, BCL6, promotes the development of certain large B-cell lymphomas (R. Dalla-Favera, Project 3);4) specific subtypes of large B-cell lymphoma have unique pathogenetic mechanisms and, likely, rational therapeutic targets (M. Shipp, Project 4);and 5) components of deregulated apoptotic and transcriptional programs in GC B-cell lymphomas can be targeted using a novel chemical strategy termed hydrocarbon stapling (L. Walensky, Project 5). The proposed projects rely heavily on input of and collaboration with investigators in the following Cores: DMA Microarray/Bioinformatics (T. Golub, Core A), Hematopathology (J. Aster, Core B), Biostatistics/Clinical Trials (D. Neuberg/A. Freedman, Core C) and Administration (M. Shipp/K. Rajewsky, Core D). In this PO1, we will utilize carefully designed murine models of GC B-cell lymphomas and highly informative primary human tumors and cell lines to define the most important molecular events in these diseases. Our long-term goal is to identify predisposing factors and molecular bases for the development of GC B-cell lymphomas, improve the diagnosis of specific entities, refine our prognostic assessments and credential rational targets for more effective and specific therapeutic intervention.